This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. InhA is the enoyl-acyl carrier protein reductase involved in type II fatty acid biosynthesis (FAS II) of Mycobacterium tuberculosis. The current TB drug INH has been shown to target InhA, and many FAS II enoylreductases from other organisms are also validated drug targets. The novel InhA inhibitors developed in our group utilize a different mechanism of inhibition from INH and can bypass INH resistance, and they are slow binding inhibitors that are expected to show better in vivo efficacy because of long residence time. We are using crystallography to study the structural basis of slow inhibition. Correlation of ordering and conformation of the InhA substrate binding loop with binding kinetics will be investigated and such information will be used for designing inhibitors with better binding kinetics.